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Human Molecular Genetics Advance Access originally published online on September 15, 2006
Human Molecular Genetics 2006 15(20):3034-3040; doi:10.1093/hmg/ddl245
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A primate-specific acceleration in the evolution of the caspase-dependent apoptosis pathway

Eric J. Vallender1,2 and Bruce T. Lahn1,*

1 Howard Hughes Medical Institute, Department of Human Genetics and 2 Committee on Genetics, University of Chicago, Chicago, IL, USA

* To whom correspondence should be addressed: Tel: +1 7738344393; Fax: +1 7738348470; Email: blahn{at}bsd.uchicago.edu

Received July 27, 2006; Revised August 27, 2006; Accepted September 4, 2006

Programmed cell death, or apoptosis, plays an essential role in mammalian development, especially the development of the nervous system. Here, we systematically examine the molecular evolution of the mammalian intrinsic apoptosis program. We divided the program into its several constituent pathways and examined the evolution of each pathway in diverse mammalian taxa spanning primates, rodents and carnivores. We observed that genes involved in the caspase-dependent apoptosis pathway stood out in several ways. First, these genes display an accelerated rate of protein sequence evolution in primates relative to rodents or carnivores. Secondly, this acceleration is most pronounced along the lineage leading to humans, and it is associated with signatures of positive selection. Finally, several genes in this pathway, including APAF1, CASP9 and CASP3, have been shown to be associated with dramatic defects in neuronal cell number and brain size when mutated in mice. These observations suggest the possibility that evolutionary changes in the caspase-dependent apoptosis pathway may have contributed to brain evolution in primates and humans. Our results also lend further support to the hypothesis that genes regulating brain size during development might have played a particularly important role in transforming brain size during evolution.


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